Abstract: Adrenal pheochromocytomas (PCC) and extra-adrenal pheochromocytomas (paragangliomas, (PGL)) are rare neuroendocrine malignancies that carry high disease burden due to excessive hormone secretion by tumor cells and high probability of metastasis [1]. Metastatic disease is especially prevalent in carriers of deleterious mutations in the subunits of succinate dehydrogenase complex (SDHx), which makes this patient group the highest treatment priority [2, 3]. The absence of effective treatment for this lethal disease remains a major clinical challenge. Our preliminary analysis of the PCC/PGL metabolome in cell lines and patient tumor samples demonstrated up-regulation of the polyamine pathway upon SDHx deficiency. N- alkylated polyamine analogue N1, N11diethylnorspermine (DENSPM) offers an exciting and innovative pharmacological approach to targeting over-reactive polyamine pathway. DENSPM has been FDA approved for clinical trial use (Phase I [4, 5]), and was evaluated for treatment of breast cancer malignancies in Phase II trial [6]. In agreement with the metabolomic analysis, our preliminary data demonstrate that DENSPM polyamine analogue is highly effective at targeting PCC-derived cells, both in vitro and in the mouse xenograft model. Importantly, DENSPM appears to be remarkably potent against PCC/PGL tumor cells with a loss of the SDHx function that present the highest clinical concern. Based on our preliminary data and the follow-up work outlined in this application, an opportunity would open for a Phase II clinical trial at the University of Florida (UF) to treat patients with metastatic PCC/PGL using DENSPM as UF has an active patent on this drug. To proceed to the clinical trial it is necessary to directly compare DENSPM to the current standard of care treatment and to evaluate the relevant biomarkers, as is proposed here. We propose that augmented polyamine metabolism that we now uncovered in SDHx-deficient tumors (tissue and cells) could be a vulnerability point unique to these (and not other) tumors that could be successfully targeted pharmacologically with DENSPM. This study will put forward the first safe and effective pharmacological treatment against metastatic tumors with a loss of the SDHx function and transform the lives of many patients urgently needing treatment.